The present invention relates to a new method of treatment for the control of gastrointestinal nematode parasites in domestic animals and compositions therefor.
Gastroenteritis caused by gastrointestinal nematode parasites in domestic animals such as horses, swine, goats, cats, dogs and particularly in sheep and cattle, is one of the major disease problems faced by the breeders and considerable economic losses are incurred unless it is properly controlled. The control measures include the therapeutic and prophylactic uses of anthelmintic agents and appropriate pasture and barn managements. The principles of control are outlined by Blood and Henderson in "Veterinary Medicine", 3rd. Edition, London, Bailliere, Tindall and Cassell, 1968, pp 583-585.
Many species of gastrointestinal nematode parasites, such as, for example, species of Haemonchus, Ostertagia, Trichostrongylus, Cooperia, Nematodirus, Chabertia or Oesophagostomum may cause gastroenteritis in sheep and cattle. In sheep Haemonchus contortus and species of Ostertagia are of particular importance and cattle Ostertagia ostertagi is the prime contributor to the disease. The clinical symptoms associated with the infections caused by these parasites as well documented in "Veterinary Medicine", cited above, pp 614-628.
Nematode parasites are dependent on the host for survival and for the maintenance of the species. Infections are acquired by the animal, while grazing, by the ingestion of infective larvae (third larval stage). These infective larvae undergo in the gastrointestinal tract of the host two additional stages of larval development (fourth and fifth larval stages) before reaching maturity. The adult nematodes then produce eggs which are excreted in the faeces. The eggs hatch and the resulting larvae (first larval stage) undergo two successive free-living developmental stages, namely second and the infective third larval stages, respectively. The transformation of eggs to the third larval stage requires 1 to 6 weeks depending on the climatic conditions of the field. In the summer an average of 2 to 3 weeks is necessary for the ingested infective larvae to develop into adult nematodes. For example, dependent on field conditions eggs of Haemonchus contortus will reach the infective stage in 1 to 6 weeks and once ingested these larvae will mature 2 to 3 weeks later. Some species of gastrointestinal nematodes, for example Haemonchus contortus, are prolific egg-producers and unless the infections are rapidly controlled they contribute to the death or the unthriftiness of the hosts and also they contribute to further contaminations of the pastures. Many anthelmintic agents presently commercially-available are effective against the adult forms of these gastrointestinal nematodes and some of them are also active against their normally developing larval stages.
Outbreaks of parasitic gastroenteritis during the summer are fairly predictable and they may be easily controlled by the administration of anthelmintics. However outbreaks of parasitic gastroenteritis in cattle and sheep are not restricted to the grazing season. There are many reports of sudden gastroenteritis during the winter and spring stabling periods even though the animals were not exposed to contamination for weeks and months, see for example E. F. Johnson et al. in Can. J. Comp. Med., Vol. 20, p. 203 (1956); W.B. Martin et al. in Vet. Rec., Vol. 69, p. 736 (1957); H.C. Gibbs in Can. Vet. J., Vol. 5, p. 8 (1964); H. J. Smith et al. in Can. Vet. J., Vol. 13, p. 114 (1972). More characteristic are the phenomena of the "spring-rise" and the Type II Ostertagiasis, respectively observed in sheep and cattle. These phenomena are well documented, see example L. Ayalew et al. in Can. J. Comp. Med., Vol. 37, p. 79 (1973); L. Ayalew et al. in Can. J. Comp. Med., Vol. 37, p. 356 (1973); H. C. Gibbs in Vet. Med. Rev., p. 160 (1967); J. Armour in Vet. Rec. Vol. 86, p. 184 (1970) and H. J. Smith et al., cited above. While Type II Ostertagiasis in cattle may take place anytime during winter and may affect yearlings and adults (see H. J. Smith et al, cited above), the spring-rise phenomenon in sheep is mainly observed in lactating ewes 3 to 13 weeks after lambing. It is characterized by a dramatic increase in the number of eggs excreted in the faeces in the spring. These eggs contaminate the pastures early in the spring and constitute a major source of infection for lambs (see L. Ayalew et al., cited above). Anthelmintic agents are effective against the worms responsible for the outbreaks of parasitic gastroenteritis in winter or spring. However, the detection of the infections is often too late to prevent damages to the animals and resulting economic losses.
There is at present considerable evidence indicating that infective larvae of gastrointestinal nematode parasites that are ingested from early fall to stabling time and through winter months do not mature with the expected 2-3 weeks but instead become dormant or inhibited in their development at the fourth larval stage for up to 9 months. It is the sudden and unexpected massive maturation of these dormant or inhibited larvae which is responsible for the spring-rise in sheep and for the outbreaks of Type II Ostertagiasis in cattle or other sudden outbursts of parasitic gastroentertitis during the stabling season (see for example L. Ayalew et al., H. C. Gibbs, H. J. Smith et al. and J. Armour, respectively cited above). The presence of dormant or inhibited larvae is virtually impossible to detect, the animals failing to show clinical signs of disease and the egg counts being very low. Furthermore there are no anthelmintic agents presently effective against dormant or inhibitive larvae (see J. Armour, cited above) and consequently there are no agents capable of preventing their eventual maturation and the subsequent outbreak of parasitic gastroenteritis.
Although many explanations have been advanced (see for example J. D. Dunsmore in Nature, Vol. 186, p. 966 (1960); Anderson et al. in Vet. Rec., Vol. 77, p. 1196 (1965); E. J. L. Soulsby in "Biology of Parasites", New York, Academic Press, 1966, pp. 257-276; J. F. Michel in Int. J. Parasitol, Vol. 1, p. 31 (1971); R. V. Brunsdon in N. Z. Vet. J. Vol. 20, p. 183 (1972) and N. M. Blitz et al. in Int. J. Parasitol., Vol. 2, p. 5 (1972), the precise triggering mechanisms for the induction of inhibition or for the maturation of inhibited larvae remain unknown